Holoprosencephaly - A Neural Tube Disorder

Introduction

Holoprosencephaly is a congenital deformation in the brain due to failed division of the forebrain. It occurs during the third and sixth weeks of intrauterine development. So the brain’s frontal portion is not adequately separated into two halves, causing facial abnormalities. The affected children will have a small-sized head with other facial deformities such as cleft palate.

What Is the Incidence of this Condition?

• They occur during the early days of gestation and are often undetectable as they end in miscarriage.

• They are seen in 1 in 250 gestations but rare in live births, with an incidence of 1 in 10000 to 16000 live births.

• They are more common in females than in males.

How Is Holoprosencephaly Classified?

Depending on the separation, they are classified into three types.

• Alobar holoprosencephaly.

• Semilobar holoprosencephaly.

• Lobar holoprosencephaly.

1. Alobar holoprosencephaly:

It is the most severe form of holoprosencephaly. In this variant, there is a complete absence of the division of the forehead. Hence, the lack of midline structures of the face, brain, etc., results in severe facial anomalies. These babies die soon after birth, or they are stillborn. They are also referred to as mono ventricles as there is no fusion of the cerebral hemispheres.

2. Semilobar Holoprosencephaly:

In this variant, there is partial separation of the brain's two hemispheres. This is considered a moderate form of holoprosencephaly. In this type, the fusion is seen in the anterior region, whereas the posterior part remains separated.

3. Lobar Holoprosencephaly:

It is a mild form of holoprosencephaly. There is a separation between the two hemispheres, but they are partially divided into right and left halves.

What Is the Cause of Holoprosencephaly?

Generally, during embryonic development, the brain divides into two halves, the right and left hemispheres. But in the case of holoprosencephaly, there is an improper division of the two hemispheres, particularly in the anterior region of the forebrain. This forebrain is essential for the development of the adult brain. So any abnormalities in the forebrain may affect the physical and functional abilities.

Three factors are responsible for this condition. They are:

• Genetic mutation.

• Chromosomal abnormalities.

• Genetic syndromes.

Genetic Mutations:

Any defect in the genetic sequence may interfere with the normal functioning of the baby and cause several growth malformations. The genes that are responsible for holoprosencephaly are

SHH, SIX3,TGIF1, ZIC2, PTCH, FOXH1, NODAL, CDON, FGF8, GLI2.

Chromosomal Abnormalities:

The most common chromosomal abnormality seen in holoprosencephaly is the presence of an extra copy of chromosome 13 called trisomy 13. It is also reported in a few cases of trisomy 18 and Down’s syndrome.

Genetic:

Some genetic conditions also cause holoprosencephaly. They are:

• Hartsfield Syndrome: A rare medical condition with holoprosencephaly and malformations of the hands and feet.

• Kallman Syndrome: A genetic condition that causes the absence of puberty or delayed puberty, or secondary sexual characteristics.

• Steinfeld Syndrome: It is a congenital disorder that causes malformations of the heart, kidney, gallbladder, and holoprosencephaly.

• Smith-Lemli- Opitz Syndrome: A congenital disorder affecting many body parts.

• Stromme Syndrome: It is a genetic disorder that causes abnormalities in the head, eyes, and intestines.

What Are the Signs and Symptoms?

The clinical presentation varies in each case of holoprosencephaly, depending on the severity of the condition. However, the most common manifestations are:

• Developmental delays that hinder intellectual abilities.

• Seizure activity is reported in 40 % of the cases.

• Short stature.

• Failure to thrive.

• Small-sized head or microcephaly.

• Fluid accumulation in the brain (hydrocephalus).

• Palatal cleft and cleft lips.

• Feeding difficulties due to the presence of palatal clefts.

• Dental abnormalities, such as the presence of only one central incisor.

• Irregular sleep pattern.

• Aspiration pneumonia.

Clinical Features of Alobar Holoprosencephaly:

• Presence of only one eye (cyclopia).

• Eyes are closely spaced.

• Flattened nasal bridge.

• The cleft lip is either unilateral or bilateral.

Clinical Features of Semi-Lobar Holoprosencephaly:

• Closely spaced eyes.

• Presence of single nostrils.

• Cleft lip (median or bilateral).

• Cleft palate.

• Normal physical appearance.

Clinical Features of Lobar Holoprosencephaly:

• Bilateral cleft lip.

• Flattened nose.

• Closely spaced eyes.

• Comparatively normal physical appearance.

What Are the Risk Factors for Holoprosencephaly?

• Maternal diabetes.

• Alcohol consumption.

• Use of medications such as Retinoic acid, Aspirin, and Misoprostol.

• Presence of hereditary conditions such as trisomy 13, 18, and Down syndrome.

• Genetic syndromes include Smith-Lemi- Optiz syndrome, Meckel-Gruber syndrome, and Pallister-Hall syndrome.

How to Diagnose Holoprosencephaly?

Prenatal screening for holoprosencephaly:

Pregnant women who are at high risk (of carrying a child with holoprosencephaly) must be screened for the possibility of the disorder in the fetus. These include:

• Women with maternal type 2 diabetes mellitus (the chance of holoprosencephaly is about one percent in such pregnancies)

• Aged mothers with predisposing genetic factors.

• Consume alcohol during pregnancy.

• History of holoprosencephaly in previous pregnancies with miscarriages or stillbirths.

• Exposure to certain medications in early pregnancy.

Holoprosencephaly is often diagnosed during prenatal ultrasounds. They may show structural deformities. Mild cases of holoprosencephaly may be undetected in the ultrasound. Other diagnostic tests may be essential.

1. Magnetic Resonance Imaging and Computed Tomography: They provide detailed information about the brain structures and detect any abnormalities.

2. Ultrasound of the Brain: It is a non-invasive diagnostic procedure that uses sound waves of high frequency to picture vital organs.

3. Electroencephalography: These help to detect seizure activity in the brain.

4. Chromosomal Analysis: They help to detect the exact cause, the genetic mutation, and the errors causing holoprosencephaly.

Prenatal detailed neuro-sonography (cranial ultrasonography), invasive testing for chromosomal issues through karyotyping, microarray testing, and fetal MRI may help in the diagnosis of suspected cases of holoprosencephaly. Accurate prenatal evaluation is crucial as the imaging findings of holoprosencephaly and its severity often correlate with morbidity and mortality of the baby after birth. Therefore, prenatal screening affects the diagnosis and management of the pregnancy. Genetic counseling must be given to the parents and families of such pregnancies.

While discussing with the parents regarding the prenatal diagnosis of holoprosencephaly, the focus is often on their decision to continue the pregnancy or terminate it (during the early stages). However, if the diagnosis was made late in pregnancy, there might be no option to terminate.

Can Holoprosencephaly Be Prevented?

• Some research shows that folic acid consumption advised at least three months before conception can help prevent any neural defects in the baby.

• Exposure to specific teratogens such as retinoic acid, alcohol consumption, or other mycotoxins increases the chance of holoprosencephaly. Thus, the patients at high risk must be made aware of the risks these teratogens pose to the baby by the healthcare professional.

• Early prenatal diagnosis of holoprosencephaly is of great importance in preventing the birth of a fetus or infant with holoprosencephaly.

• Such incidences can be reduced with early diagnosis and appropriate genetic counseling of the parents and the family.

How Are They Managed?

Only palliative therapy is recommended for holoprosencephaly as there is no definitive treatment. However, supportive treatment may render relief to the affected children.

• Seizures: Anticonvulsants are used as a prophylactic regimen.

• Gastrointestinal Problems: H2- receptor antagonists, proton pump inhibitors

• Surgery: Neurosurgery may be indicated to relieve the fluid accumulation in the brain. A ventriculoperitoneal shunt is placed to prevent fluid build-up in the brain.

• Gastrotomy: A feeding tube is inserted to aid the swallowing in the baby due to the presence of a palatal cleft.

• Physical Therapy: This improves muscle activity in case of spasticity and dystonia.

• Reconstructive Surgeries: Surgical procedure done to correct the opening in the roof of the mouth (palatal cleft) and the groove in the lips (cleft lips).

What Is the Prognosis of Holoprosencephaly?

The prognosis depends on the type of holoprosencephaly. Generally, in the alobar type, the baby is either stillborn or dies soon after birth. The maximum life expectancy is six months. Babies with semilobar holoprosencephaly may survive up to one year, and in the lobar variety, many patients may survive to adulthood.

Conclusion

Holoprosencephaly in children may be challenging in terms of leading a regular life. They require consistent, lifelong follow-ups. Patients may require multiple surgeries to correct physical deformities. Parents and family members are given counseling to help their children with holoprosencephaly.